Hereditary spastic paraplegias (HSPs), also known as Strumpell-Lorrain disease, are a heterogeneous group of monogenetic neurodegenerative disorders where the unifying clinical presentation is that of progressive spasticity and paraplegia.(1) Inheritance follows autosomal-dominant (AD), autosomal-recessive (AR) or X-linked patterns. The classification is based on the affected genes.(2, 3) So far more than 80 causal genes or loci have been detected and resulted in a spastic paraplegia gene (SPG) classification.(4, 5) The histopathological feature of HSPs is a length-dependent axonal degeneration of motor and sensory fibers within the corticospinal tract and the dorsal column.(6, 7)
Spastic Paraplegia 39 (SPG39), an AR SPG, was first described in 2008 by Rainier et al.(8) and is characterized by a childhood onset of progressive spasticity of the lower limbs and progressive weakness of the upper and lower limb muscles.
The phenotype of SPG39 corresponds to SPG20, an AR form of HSP with lower motor neuron involvement, and to organophosphorous compound-induced delayed neuropathy (OPIDN) with distal axonal degenerations.(8–10) SPG39 is caused by mutations in PNPLA6, a gene encoding neuropathy target esterase (NTE). Interestingly, mutations of PNPLA6 have also been found to cause other rare hereditary neurodegenerative diseases such as Gordon-Holmes, Boucher-Neuhauser, Laurence-Moon and Oliver-McFarlane syndrome.(11–13)
Rainier et al.(8) reported two families in which affected subjects developed a childhood onset progressive spastic weakness of lower limbs and wasting of distal upper and lower limb muscles. In the consanguineous family, affected subjects carried a homozygous mutation in the PNPLA6 gene c.3034A > G, p.(M1012V) that was shown to alter the catalytic domain of the encoded protein NTE. Moreover, in the non-consanguineous family affected subjects were compound heterozygotes where one allele had a missense mutation c.2669G>A, p.(R890H) and the other allele had an insertion mutation c.2946_2947insCAGC, p.(S982fs1019). Both variants cause an impaired enzymatic function of NTE.
In 2014, Synofzik et al.(11) reported a family with HSP harboring the compound heterozygous variants c.787G>A, p.(Val263Ile) and c.2519G>A, p.(Gly840Glu) in the PNPLA6 gene. Affected subjects presented with spasticity, hyperreflexia of lower extremities, positive Babinski’s sign and a mild motor neuropathy.
Yoon et al.(14) presented a sole patient with a pure spastic paraplegia phenotype characterized by motor delay and gait abnormalities with falls. This patient was heterozygous for the variant c.2944_2947dup, p.(Arg983ArgfsX86) of the PNPLA6 gene.
We here describe a large kindred with two hitherto undescribed mutations in the PNPLA6 gene. Their clinical phenotype was novel as, in addition to spastic paraplegia, they had a marked cerebellar oculomotor dysfunction.
Case Presentation
S1 (Subject 1), the index subject, was a 29-year-old male presenting with benign peripheral paroxysmal vertigo. Routine neurologic examination revealed marked gait disturbance for which the patient had never sought medical advice. He reported normal milestones during childhood and worked as a skilled specialist in manufacturing.
On examination he had grossly spastic gait with normal Romberg test and brisk muscle stretch reflexes with sustained ankle clonus. However, Babinski’s sign was negative. His muscles were neither weak nor atrophic. Oculomotor testing revealed massive saccadic pursuit movements. There was coarse nystagmus evoked by upward and horizontal gaze. On downward gaze, however, the direction of the nystagmus was upward (to his forehead) (Additional file 2; Additional file 3). There was no nystagmus in primary position. Rebound nystagmus could easily be elicited. HIT (head impulse test) according to Halmagyi showed normal VOR (vestibular ocular reflexes), but the suppression of the VOR by fixation was markedly impaired. Optokinetic nystagmus was reduced. Despite these prominent findings the patient had no subjective visual complaints. There was no ataxia of gait, the upper limbs or of speech. The remainder of the neurologic examination was inconspicuous. In particular there was no sensory, autonomic or cognitive dysfunction.
In S2 (subject 2), his 35-year-old sister, an office employee with good cognitive abilities, a marked gait disturbance had been present from early childhood with a very slowly progressive course. In terms of quality, her neurological findings were identical to subject S1, however, somewhat more pronounced. At the age of around 18 years, she developed secondary amenorrhea.
The father, S5 (subject 5), of S1 and S2 had no complaints. On examination he had sustained ankle clonus without Babinski’s sign. Gait and balance were normal and there was no oculomotor disturbance.
The same was true for the mother, S4 (subject 4), in whom ankle clonus was present but exhaustible.
S3 (subject 3), the 71-year-old paternal uncle of S1 and S2, became symptomatic only in his early fourties with gait disturbance and vertigo on head movement. On examination there was gaze evoked nystagmus to both sides and upwards but not downwards, saccadic pursuit movements, moderately impaired VOR and impairment of fixation-induced suppression of the VOR (corresponding with impaired reading on smooth sinusoid head movements).
Gait was clumsy but not spastic or atactic; Romberg test was normal. Muscle strength was normal without any atrophy, but knee and ankle jerks were markedly increased with sustained ankle clonus. Babinski’s sign was negative. There were no sensory findings.
The son of S3 had no complaints and was normal on thorough neurological examination.
In the extended family one female cousin in the paternal line of S1 and S2 had died from bulbar-onset amyotrophic lateral sclerosis at the age of 33, and another cousin had a well-founded diagnosis of multiple sclerosis. Genetic material was not available from these two subjects.
Paraclinical Findings
Routine blood tests were done in S1, S2 and S3 and did not yield any systematic abnormalities. Hormone status was compatible with hypogonadotropic hypogonadism in S1 and S2.
In the CSF, taken from S1, routine parameters as well as neurofilament light, total tau and phosphorylated tau were unrevealing.
In S1 and S3, standard MRI (Siemens Avanto; 1,5 Tesla) of the brain and the entire spinal cord was normal without cerebellar or spinal cord atrophy. MRI or other radiological examinations were not available from the other family members.
In VNG (videonystagmography) of S1 and S2 the most prominent finding was pathologic fixation suppression of the VOR (Fig. 2). Nerve conduction studies, done in S1 and S2, were conspicuous only for increased F-latencies in the peroneal and tibial nerves of only S1. Needle EMG was normal. In S2, magnetic evoked potentials showed increased central motor conduction times to the distal legs while there were no responses in S1.
Ophthalmologic examination, done in S2, was normal including OCT (optical coherence tomography). Degree of relationship, genotype and clinical phenotype of subjects are given in Table 1 (more detailed information Additional file 2).